Triple vs Quad, Cocktail?

May 29, 2001

Hello Dr. Cohen,

I need an opinion or let's say an educated guess. :)

Background:
I was diagnosed in '99 with a base line VL of 750K, CD4 300.
Started first line regiment with Sustiva and Combivir. Went off AZT a few months later...due to severe anemia.
The decline in viral load was dramatic...but did not reach UD-and with the Nuke switch-I finally settled on SUSTIVA-EPIVIR & ZIAGEN. Zerit was tried but I had FAST neuropathy and no real benefit viralogically for the few months I was on it.
So for the last year...I have had a viral load...bumping around...150, 800, 50 - I mean it has been all over the place...but never really over 1000. CD4 has climbed up to 890.
I have been compliant on my dosing of meds.

Well, my doc is in Research and he is a little wary that I have not reached or stayed at UD levels. He suspects Epivir as being the weak link. Not wanting to wait for a 1000 VL count in the future? -to Geno-
he is going to put me on the new nuke TENOFOVIR on expanded access. His logic is that he really wants to preserve the potency of my NNRTI, Sustiva and not have it compromised by weak nukes, as he suspects Epivir (3TC). Fine. I do like that. He mentioned that he wants to keep me on Epivir with the Tenofovir. I complained about all those nukes (3) plus the sustiva-toxing me out...I do notice side efx from my meds-nothing major...but I feel negative things happening to my body (fatigue, choles, Bone mass loss, etc)-

So my QUESTION (finally) IS-
If Tenofovir does get me UD-can I ditch the Epivir?

Mike
Not a Quad fan-just want a good triple play home run.
Thank You.

Response from Dr. Cohen

Well, as you point out - this question - about the ongoing potency of Epivir or 3TC if there is or might be resistance - is one we have had for several years. And there might finally be a clinical study set up to get at this question. So let me share the few things we know at this point.

First - a definition for others that UD is undetectable, meaning here a viral load below 50 copies. That is our target since a regimen that suppresses HIV's growth to that extent appears to be durable in how long this will last - and way more durable that a regimen where the viral load is close to, but not below 50. And so our assumption is that while your response to treatment is an excellent one, one of these days, HIV will finally undo the benefits of these meds. HIV is still growing (and that's what a viral load of 110 or 304 is -- 304 copies of HIV per ml of blood) - and we have learned that when HIV can grow it often creates more and more mutations that allow it to eventually ignore the medications slowing it down. So your viral load might one day be closer to 750 thousand where you started from.

Now - your viral load is near but not below 50. And bouncing around. Enough suppression to allow your immune system to thrive and regrow, for now. Should you do more? As you point out, the reason we worry about even low amounts of HIV growing is that at this low level HIV can create resistance. Now, there are resistance assays that might measure resistance even at this low viral load - you might ask if you can get access to a "LiPa" assay which may be of useful here. But let's assume you do have resistance - from many studies it is true that HIV can most readily create resistance to epivir/3TC - called the 184V mutation. Another concern is not only does this lead to less potency from 3TC - it is the first link in the chain to seeing resistance to the ziagen/abacavir. And our concern with the nonnukes, like Sustiva, is that they too are vulnerable to resistance even at low levels of growing HIV - and some concern is reasonable here that you might have some degree of resistance to this med as well. Which is why a resistance assay would be of interest here - to see if that has happened as well.

But if we assume that there is resistance to only the epivir, is there any benefit to the medication? Here is one way in which our meds differ. The key is to understand that HIV can pay a price to create resistance. And the price it pays to create this 184V mutation is pretty hefty - it reduces growth by about a half a log. Which is pretty useful - especially since it is generally understood that it is among the safest meds we use as well. So, since there is this half log activity even after resistance, most clinicians leave the epivir on board when doing what you are doing - intensifying the regimen by adding a single agent such as tenofovir. (For those who don't know this newer drug - it is still experimental at this time but in this setting also adds somewhere between a half log and one log drop in viral load.)

However, the story is a bit more complex, of course. As I mentioned, both epivir and ziagen can create the 184V mutation. IF selecting for HIV with this mutation is what leads to the ongoing effect from epivir, then perhaps having ziagen on board should actually create the same mutation, since it too selects for this 184V mutation. And if so, it too might have this half log drop, even without the epivir around. It remains uncertain, however, if your viral load will be the same with or without the epivir in the presence of ziagen, and since epivir is among the safest, we often just leave it there. Of the toxicities you mention at this point, our assumption is that none of them would improve in the absence of the epivir, but again, this is partly an assumption since people do react differently...

So in sum, yeah, most clinicians would just add the tenofovir. Could you take just three meds - perhaps. And in a few years we should have the info needed to know rather than guess at what you can do, and if you can or cannot drop the epivir...

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